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Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.

Publication ,  Journal Article
Carol, H; Morton, CL; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, C; Smith, MA; Houghton, PJ; Lock, RB
Published in: Pediatr Blood Cancer
December 15, 2010

BACKGROUND: GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: GSK690693 was tested in vitro at concentrations from 1 nM to 10 µM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily × 5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10 µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity. CONCLUSIONS: GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.

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Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

December 15, 2010

Volume

55

Issue

7

Start / End Page

1329 / 1337

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Proto-Oncogene Proteins c-akt
  • Oxadiazoles
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice, SCID
  • Mice, Nude
  • Mice, Inbred NOD
  • Mice, Inbred BALB C
 

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Carol, H., Morton, C. L., Gorlick, R., Kolb, E. A., Keir, S. T., Reynolds, C. P., … Lock, R. B. (2010). Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatr Blood Cancer, 55(7), 1329–1337. https://doi.org/10.1002/pbc.22710
Carol, Hernan, Christopher L. Morton, Richard Gorlick, E Anders Kolb, Stephen T. Keir, C Patrick Reynolds, Min H. Kang, et al. “Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.Pediatr Blood Cancer 55, no. 7 (December 15, 2010): 1329–37. https://doi.org/10.1002/pbc.22710.
Carol H, Morton CL, Gorlick R, Kolb EA, Keir ST, Reynolds CP, et al. Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2010 Dec 15;55(7):1329–37.
Carol, Hernan, et al. “Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 55, no. 7, Dec. 2010, pp. 1329–37. Pubmed, doi:10.1002/pbc.22710.
Carol H, Morton CL, Gorlick R, Kolb EA, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C, Smith MA, Houghton PJ, Lock RB. Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2010 Dec 15;55(7):1329–1337.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

December 15, 2010

Volume

55

Issue

7

Start / End Page

1329 / 1337

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Proto-Oncogene Proteins c-akt
  • Oxadiazoles
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice, SCID
  • Mice, Nude
  • Mice, Inbred NOD
  • Mice, Inbred BALB C